Process of preparing cephalosporanic acid ester derivatives

ABSTRACT

A process of preparing a Δ 3  -cephalosporanic acid ester derivative which comrises reacting a cephalosporanic acid sulfoxide ester derivative with thionyl halide or a phosphorous halide. 
     The compounds prepared by the process of this invention are useful as intermediate compounds for preparing cephalosporin antibiotics and the compounds themselves are also potential antibacterials.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process of preparing cephlosporanicacid ester derivatives and more particularly it relates to a process ofpreparing Δ³ -cephalosporanic acid ester derivatives represented by thegeneral formula ##SPC1##

Wherein R¹ and R², which may be the same or different, each represents aunivalent group other than a hydrogen atom, said R¹ and R² may becombined to form a divalent group, and R³ represents an organic esterresidue which can be released under mild conditions by which comprisesreacting a cephalosporanic acid sulfoxide ester derivative representedby the general formula ##SPC2##

Wherein R¹, R², and R³ have the same meaning as in general formula I,and with the halogen compound represented by a general formula

    SOX.sub.2                                                  III-A

or

    PX.sub.3                                                   III-B

wherein X represents a halogen atom.

The desired compounds of this invention are useful intermediatecompounds which can be converted to cephalosporin antibiotics and whenthe divalent group formed by the combination of R¹ and R² in generalformula I is, for example, a1,1-dimethyl-3-phenyl-2-nitroso-4-oxo-2-azatetramethylene group, thatis, when the desired compounds of this invention is the compounds of theformula, ##SPC3##

The products can be converted to cephalexin having the formula ##SPC4##

Which is useful as an antibiotic by treating the compound with an acidand then water. Also the desired compounds of this invention arepotential antibacterials themselves.

In the process of producing a Δ³ -cephalosporanic acid or an esterthereof, a method is known in which the sulfoxide of a 7-protectedamino-Δ³ -cephalosporanic acid sulfoxide or an ester thereof is reducedby reacting it with phosphorus trichloride (see, Japanese Patent No.21,111/'72).

However, it has not yet been known that the sulfoxide reduction can besimilarly applied to a compound having a hydroxy group and a methylgroup at the 3-position. On the other hand, it is known that when acompound which has a hydroxy group and a methyl group at the 3-positionbut the sulfur atom at the 1-position of which has not been oxidizedreacts with thionyl chloride three kinds of compounds, that is, acompound in which the hydroxy group has been substituted by a chlorineatom and a small amount of a compound having a methyl group at the3-position and a double bond between the 3-position and the 4-positionand other compounds have been obtained (see, "Journal of the AmericanChemical Society"; 94(20), 7169-7170(1972)). Therefore, even if personsskilled in the art may consider that by reacting a compound having ahydroxy group and a methyl group at the 3-position and an oxidizedsulfur atom at the 1-position with thionyl chloride or phosphoroustrichloride, a compound having a methyl group at the 3-position and adouble bond between the 3-position and the 4-position is obtained, theywould as a matter of course presume that the amount of the compound thatis obtained is small.

Under such a technical level, the inventors have discovered that when astarting material of formula II is caused to react with a halogencompound such as thionyl chloride (formula III-A, X is chloride) orphosphorus trichloride (formula III-B, X is chloride), a product offormula I only is obtained unexpectedly without accompanied by theformation of by-products.

That is, according to the process of this invention, the desiredproducts of general formula I can be obtained by a quite simple manner.

As groups R¹ and R² of general formula II representing the startingmaterial used in this invention, there are various groups other thanhydrogen atom and specific examples of the univalent groups representedby R¹ and R² are a straight or branch alkyl chain or a cyclic alkylgroup such as a methyl group, an isobutyl group, a cyclohexyl group,etc.; an aralkyl group such as a benzyl group, a phenethyl group, afurylethyl group, a pyridylmethyl group, etc.; a substituted alkyl groupsuch as a trifluoromethyl group, a methoxymethyl group, a phenoxyethylgroup, a benzylthioethyl group, etc.; an aryl group such as a phenylgroup, a naphthyl group, a quinolyl group, a tolyl group, ap-nitrophenyl group, etc.; an acyl group such as an acetyl group, aphenylacetyl group, a cyclohexylacetyl group, a benzoyl group, anα-phenoxyacetyl group, etc.; a carbamoyl group such as an acetamidogroup, a N-methylbenzamido group, etc.; a dimethoxyphosphinyl group; atrimethylsilyl group; and the like. Also, specific examples of divalentgroups formed by the combination of R₁ and R₂ are an arylidene groupsuch as a salicylidene group, a benzylidene group, etc.; a phthaloylgroup, a succinyl group; and the like.

Any organic ester groups which do not contribute to the reaction may beemployed as the residue represented by R³ of general formula II.Examples of such a group are a 2,2,2-trichloroethyl group, atriphenylmethyl group, a bis(p-methoxyphenyl)methyl group, a benzhydrylgroup, a phenacyl group, a p-bromophenacyl group, a3,5-di-tert-butyl-4-hydroxybenzyl group, a phthalimidomethyl group, abenzyl group, a nitrobenzyl group, a p-toluenesulfonylethyl group, etc.

In the practice of this invention, a starting material of generalformula II is dissolved or suspended in an inert solvent such aschloroform, dimethylformamide, methylene chloride, carbon tetrachloride,etc. and after cooling the solution or the suspension to a lowtemperature, preferably to temperatures lower than 0°C., the halogencompound represented by formula III-A or III-B is added to it in anexcessive amount, preferably in an amount more than double the molaramount of the starting material.

It is desirable for the smooth progress of the reaction to add atertiary base such as pyridine, N-methylmorpholine, N,N-dimethylaniline,triethylamine, etc., to the reaction system in an amount more than theequimolar amount of the compound of the formula III-A or III-B.

The desired product of the formula I may be isolated and purified by anordinary chemical treatment such as extraction, concentration, columnchromatography, and the like.

The following examples are intended to illustrate the process of thisinvention but not to limit in any way.

EXAMPLE 1

In 15 ml. of anhydrous chloroform was dissolved 500 mg. of benzhydryl3-hydroxy-3-methyl-7-phthalimidocepham-4-carboxylate sulfoxide and afteradding to the solution 558 mg. of N-methylmorpholine and 253 mg. ofphosphorus trichloride successively under ice cooling, the mixture wasstirred for 2 hours. The reaction mixture obtained was washed withwater, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The concentrate thus formed was subjected to a silicagel column chromatography (diameter 1.8 cm., height 12 cm.). The productwas then eluted using a mixture of benzene and ethyl acetate of 9 : 1 involume ratio as an eluant. The effluents were combined and concentratedunder reduced pressure Then, by adding ether to the concentrate, 210 mg.of a white powder of benzhydryl 3-methyl-7-phthalimido -Δ³-cephem-4-carboxylate was obtained.

The chemical structure of the product estimated by infrared absorptionspectra thereof coincided with the assumed chemical structure.

Nuclear magnetic resonance spectra (in CDCl₃): δ: 2.20 (3H, S), 2.64,2.90, 3.55, 3.81 (A.B pattern, 2H), 4.96 (d, J = 4.5, 1H), 5.62 (d, J =4.5, 1H), 6.85 (1H, S), 7.0-7.9 (14H).

EXAMPLE 2

A. In 20 ml. of chloroform was dissolved 620 mg. of benzhydryl3-hydroxy-3-methyl-7-(2,2-dimethyl-3-nitroso-4-phenyl-5-oxo-1-imidazolidinyl)cepham-4-carboxylateand 10 ml. of chloroform containing 142 mg. of perbenzoic acid was addedto the solution under ice cooling. After the reaction was over, thereaction mixture was concentrated under reduced pressure and thecrystals of benzhydryl3-hydroxy-3-methyl-7-(2,2-dimethyl-3-nitroso-4-phenyl-5-oxo-1-imidazolidinyl)cepham-4-carboxylatesulfoxide thus precipitated were recovered by filtration and washed wellwith ether. The amount of the product obtained was 610 mg.

Infrared spectrum: 1003 cm⁻ ¹ (S → O). Nuclear magnetic resonancespectra (in D₆ -DMSO): δ: 1.09 (3H, S), 2.0 (3H, S), 2.08 (3H, S), 2.75,2.96, 3.32, 3.53 (AB pattern, 2H), 4.40 (1H, S), 4.75 (1H, d, J = 4.5),5.65 (1H, S), 5.72 (1H, d, J = 4.5), 6.94 (1H, S), 7.2-7.6 (16H).

(B). In 15 ml. of anhydrous dimethylformamide was suspended 500 mg. ofthe product obtained in Example 2-(A) and after cooling the solution totemperatures lower than -20°C., 450 μ 1. of pyridine was added to thesuspension. Then, after cooling the mixture to temperatures lower than-30°C., 165μ1. of phosphorus trichloride was added to the mixture.

The temperature of the reaction mixture was gradually raised to 0°C.over a period of about 1 hour and then the mixture was stirred for 2hours at room temperature. To the reaction mixture was added 50 ml. ofmethylene chloride and the resultant mixture was washed three times eachtime with 20 ml. of water. The organic solvent layer formed wasseparated, dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The concentrate was then subjected to a silicagel column chromatography (diameter 1.8 cm., height 10 cm.). The productwas eluted using a mixture of benzene and ethyl acetate of 3 : 1 byvolume ratio as an eluant. The effluents were combined, and concentratedunder reduced pressure. Then, by adding ether to the concentrate, 207mg. of the white precipitate of benzhydryl3-methyl-7-(2,2-dimethyl-3-nitroso-4-phenyl-5-oxo-1-imidazolidinyl)-.DELTA.³-cephem-4-carboxylate was obtained.

The chemical structure of the product estimated from the infraredabsorption spectra of it coincided with the assumed chemical structure.

Nuclear magnetic resonance spectra (in CDCl₃): δ: 1.93 (3H, S), 1.98(3H, S), 2.20 (3H, S), 2.49, 2.74, 3.40, 3.65 (AB pattern, 2H), 4.82(1H, d, J = 4.2), 4.99 (1H, d, J = 4.2), 5.45 (1H, S), 6.94 (1H, S),7.2-7.5 (15H).

EXAMPLE 3

In 20 ml. of anhydrous chloroform was suspended 1 g. of the productobtained in Example 2-(A) and then 770 mg. of pyridine and 389 mg. ofthionyl chloride were added to the suspension under ice cooling. Afterstirring the mixture for 22 hours at room temperature the reactionmixture was washed four times each time with 30 ml. of water, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.Then, by treating the concentrate through a column chromatography as inExample 2-(B), 410 mg. of benzhydryl3-methyl-7-(2,2-dimethyl-3-nitroso-4-phenyl-5-oxo-1-imidazolidinyl)Δ³-cephem-4-carboxylate was obtained.

What is claimed is:
 1. A process of preparing a Δ³ -cephalosporanic acidester of the formula ##SPC5##wherein R¹ and R² which may be the same ordifferent, each represent a member selected from the group consisting ofa straight or branched chain alkyl group of 1 to 4 carbon atoms, acyclohexyl group, a benzyl group, a phenethyl group, a furylethyl groupa pyridylmethyl group, a trifluoromethyl group, a methoxymethyl group, aphenoxyethyl group, a benzylthioethyl group, a phenyl group, a naphthylgroup, a quinolyl group, a tolyl group, a nitrophenyl group, an acetylgroup, a phenylacetyl group, a cyclohexylacetyl group, a benzoyl group,an alpha-phenoxyacetyl group, an acetamido group, a dimethoxy phosphinylgroup and a trimethyl silyl group and R¹ and R² taken together forming amember selected from the group consisting of a salicylidene group and abenzylidene group, a phthaloyl group, a1,1-dimethyl-3-phenyl-2-nitroso-4-oxo-2-azatetramethylene group andsuccinyl group, and R³ represents a member selected from the groupconsisting of a 2,2,2-trichloroethyl group, a triphenylmethyl group, abis(p-methoxyphenyl) methyl group, a benzhydryl group, a phenacyl group,a p-bromophenacyl group, a 3,5-di-tert.-butyl-4-hydroxybenzyl group, aphthalimidomethyl group, a benzyl group, a nitrobenzyl group, and ap-toluenesulfonylethyl group, comprising the steps of adding to amixture of cephalosporanic acid sulfoxide ester of the formula: ##SPC6##in which R¹, R² and R³ are as defined above in an inert solvent undercooling an excessive amount of a compound of the formula

    PX.sub.3

in which X is halogen and a more than equimolar amount with respect toPX₃ of a tertiary base, and recovering said Δ³ -cephalosporanic acidester.
 2. The process as claimed in claim 1 wherein said reaction isconducted in the presence of an inert organic solvent.
 3. The process asclaimed in claim 2 wherein said inert organic solvent is chloroform,dimethylformamide, methylene chloride, or carbon tetrachloride.
 4. Theprocess as claimed in claim 1 wherein said reaction is conducted undercooling to temperatures lower than 0°C.